Synthesis of 4, 5-diamino-6-dimethylamino pyrimidine



United States Robert Bruce Angier, Pearl River, and :Joseph WilliamMarsico, Nanuet, .N. Y., assignors ,to American Cyan: amid Company, NewYork, ;N- a corporation of Maine I No Drawing. Application November 18,1954, Serial No. 469,829

5 Claims. (Cl. 260-256.4)

This invention relates to a new class of substituted pyrimidines. Moreparticularly, this invention is concerned with4,5diamino-6-substituted-aminopyrimidines, salts thereof and methodsfortheir preparation.

The new pyrimidines of this invention may be represented .by thefollowing structural'formula': 9

tyl-N-phenylamino, N-isopropyl-N-p-chlorophenylamino;-

dialkylamino such as .dimethylamino, diethylam'ino; dipropylamino,dibutylamino, and .diisopropylamino;:N;N- pentamethyleneamino such aspiperidino .and 3-ch'loropiperidino; N,N-oxapentamethyleneamino such .asmorpholino and 2-chloromorpholino.

Inasmuch .as the new zpyrimidines .of the :above formula are aminebases, they form acid-addition salts with strong acids as illustrated byhydrochloric acid, sulfuric .acidand p'icric acid. These acid additionsalts are valuable, particularly in the isolation and purification ofthe new pyn'midines and it is intended that they also constitute a partof the present invention.

The new substituted pyridimine compounds of this invention are useful inthe field of organic synthesis. They can, for example, be employed asintermediates in the preparation of substituted purines by the processdisclosed in co-pending U. S. application S. N. 469,828, now abandoned,by Leon Goldman and Joseph W. Marsico filed concurrently herewith andwhich comprises heating a 4,5-diamin0-6-substituted-aminopyrimidine inthe presence of acetic anhydride and ethylorthoformate to effect ringclosure. The resulting 6-'substituted aminopurine can be condensed, inthe form of its chlorornercury salt, with a fully acylated haloaminosugar to produce the biologically active, trypanosomicidalaminonucleosides. For example, 6-dimethylaminopurine as thechloromercury salt may be reacted with 1acetyl-2,5-dibenzoyl-3-acetamino-D-ribofuranoside as the titanium tetrachloride complex toobtain 6-dimethylamino-9-(3'-amino-}8-D-ribofuranosyl)purine afterdeacylation, in accordance with the procedure of Baker et al., J. A. C.S. 76, 4044 (1954). The compound has further utility as an intermediatefor preparing the antibiotic puromycin in that it can be rep 2 actedwith the N-blocked carboxy-activated form of pmethoxyphenylalanine toyield 6-dimethylamino-9-(3-pmethoxyphenylalanylamino-p-D-ribofuranosyl)purine, a compound found ito be powerful Pineliminating "trypano seamsof the evansiand erucei groupsfriomthe bloodkof infected animals. Themethodforcondensing theami'rio nuclec-si'de with amino acids isdescribed by Bakeretlal; in J. A. C. S. 76,2838 '(1954). i l

A wide varietyof :methods may be emp'l'oyed by those skilled in the .artfor the preparation 0f the compounds of this invention. However, we havediscovered :apar ticularlyuseful method and it is 'intended'thatthismethod also constitute a part of'the present'invention. in -accord; ancewith our process 2-alkylrnercapo l,5#diamino 6-substituted-aminopyrimidine is trea ted with a IoW tempra ture Raney nickelcatalyst whereby the substituted mercapo group is replaced by hydrogen.This new reaction can n illustrated by jthe followingeguationt V whereinR has the values assigned above and R1 j -is a lower alkyl group, as forexample, CH3, .C H5,j C3H7 0r C4H9.

Low temperature-Raney nickel catalyst is a material well known to thoseskilled in the art. It is prepared in a manner identical to theprocedure usuallyemployedfor the preparation of Raney nickel except thatthe tempera; ture after the addition of the alloy is maintained atabout80 C. or preferably even lower, for instance, C. The lowtemperature-Raney nickel thus prepared contains a large percentage ofhydrogen .(the exactpercentage can readily be determined .by sirnpletests well known to those; skilled in the art) so that the catalyst canbe employed in reduction reactions without thefurther addition of,h ydrogeni. The ,low temperature-.Raney nickel catalyst should be employedin an amount at. least.suflicient tq furnish the quantity of hydrogentheoretically necessary for the desired reduction and preferably .aconsiderable excess. A 2 to 10-fold excess has been found ito.giveexcellent results. I

The new reaction of this invention mayladvantageously' be conducted in.an inert solvent aslillu strated .by. the lower alcohols, glycol,methyl Cellosolve, gly col ethers and aromatic hydrocarbon solvents.Methyl Cellosolve is the preferred solvent. The reaction can beconducted at any convenient temperature, for instance from about 25 C.to 150 C., although best results are usually obtained at temperatures inthe range from 60 C. to 100 C. At 25 C. the reaction is, in mostinstances, substantially complete in from about 1 to 24 hours, and atabout C.

r the reaction is usually substantially complete in about A to 1 hour.

The following examples are submitted as being illustrative of ourinvention. They are not intended, however, to limit the scope thereof.

Example I Two parts 'by weight of 2-methylmercapto-4,5-diamino-6-dimethylamine-pyrimidine was dissolved in 30 parts by volume of methylCellosolve and to this was added a slurry product had amelting point of150 C. to 152 C. Recrystallization from benzene gave4,5-diamino-6-dimethylaminopyrimidine, having a melting point of 156 C.to 158. C.

' Example II 20 parts by weight of 2-methylmercapto-4,S-diamino-G-dimethylamino-pyrimidine was dissolved by warming in 200 parts by volumeof methyl Cellosolve. To this was added a slurry of 200 parts by weightof Raney nickel catalyst in 200 parts by volume of methyl Cellosolve.The mixture washeated on a steam bath with stirring for one hour. Thecatalyst was filtered off while hot and then washed with methylCellosolve and water. The filtrate and washings were combined andconcentrated to dryness under reduced pressure. The residual solid4,5-diamino-6- dimethylamino-pyrimidine was recrystallized from 350partsby volume of benzene to yield the purified product, meltingv at,157 C. to 159' C.

' Example 11! 2 methylmercapto 4 amino 6 methylamino pyrimidine maybe'nitrosated to 2-methylmercapto-4- amino-5-nitroso-6-methylaminopyrimidine by treatment with nitrous acid. Reduction of this compoundwith sodium hydrosulfite yields 2-methylmercapto-4,S-diamino--methylamino-pyrimidine which may be dissolved in ethyl alcohol and themixture heated at steam bath temperature in the presence of Raney nickelcatalyst for one hour. The product, 4,5-diamino-6-methylaminopyrimidinemay be separated by filtration and recrystallized from benzene.

Example IV 2 methylmercapto 4 amino 6 phenylamino pyrimidine may benitrosat'ed to 2-methylmercapto-4-amino-5-nitroso-6-phenylamino-pyrimidine by treatment with nitrous acid.Reduction of this compound with sodium hydrosulfite yields2-methylmercapto-4,S-diamino- 6-phenylamino-pyrimidine. This compound,upon dissoluti on in methyl Cellosolve and heating at steam bathtemperature for a period of about one hour in the presence of Raneynickel catalyst yields 4,5-diamino-6-phenylarnin0- pyrimidine. Thisproduct may be separated from the reaction mixture 'by filtration andrecrystallized trombonzene.

The invention may be further illustrated by the following examples. Eachof these compounds may be prepared in accordance with the conditions setforth in Example I, employing corresponding2-alkylmercapto-4,5-diamino-G-substituted pyrimidines as startingmaterials:

4,5-diamino-6-me-thylamino-pyrimidine 4,S-diamino-fidiethylamino-pyrimidine 4,5-diamino-6-diisopropylamino-pyrimidine4,5-diamino-6-dip-ropylamino-pyrimidine 4,5diamin0-6-butylaminmpyrimidine4,5-diamino-fi-Nmethyl-N-benzylaminopyrimidine4,5-diamino-6-N-propyl-N-benzylaminc-pyrimidine4,541iamino-6-phenylamino-pyrimidine4,5-diamino-6-m-chlorophenylamino-pyrimidine4,5-diamino-6-piperidino-pyrimidine 5 iavnin o-6-N-ethylN-phenyl-pyrimidine 4,5-diamino-6N-isopropyl-N-p-chlorophenyhpyrimidine4,5-diamino-fi-morpholino-pyrimidine 1.. A method of preparing eralformula:

compounds having the genin which R a member selected from the groupconsisting of di-lower-alkylamino and mononuc-lear-arylamino radicalsand salts thereof with strong acids, which comprises contacting with alow temperature Raney nickel catalyst, a compound selected from thegroup consisting of a 2- methylmercapto 4,5 diamino 6 di loweralkylamino-pyrimidine and p a 2-methylmercapto-4,S-diamino6-mononuclear-arylamino-pyrimicline.

2. The method which comprises contacting a Z-methylmercapto 4,5 diamino6 di lower alkylamino pyrimidine with a low temperature Raney nickelcatalyst, said contact being efiected in an inert solvent and at atemperature of from about C. to C.

3. A method which comprises contacting a Z-methylmercapto 4,5 diamino 6dialkylamino pyrimidine with a low temperature Raney nickel catalyst,said con tact being effected in an inert solvent and at a temperature offrom about 60 C. to100" C. p

4. The method of claim 3, when the Z-methylmercapto- 4,5-diamin06-dialkylaminopyrimidine is Z-methylmercapto-4,5diamin0-6-dimethylamino-pyrimidine.

5. The method of claim 3, when the Z-methylmercapto- 4,5-diamino-6dialkylamino-pyrimidine isZ-methylmercapto-4,5-diamino6-diethylaminopyrimidine.

References Cited in the tile of this patent UNITED STATES PATENTS2,407,204 English et al. Sept. 3, 1946

1. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA: